The long term objective of this project is the development of animal and in vitro models to elucidate the host-parasite interactions controlling the relationship between the nematode, Strongyloides stercoralis, and its hosts (man, primates and dogs), In these interactions the host usually prevails, resulting in a well-tolerated, self-limited infection. Sometimes neither host nor parasite prevails and a highly persistent, chronic infection is maintained. Occasionally the controls on parasite abundance and distribution fail, resulting in massive hyperinfection sometimes with highly invasive, often fatal, disseminated infection. More specifically, building on our own and other recent advances, we propose: (1) In vivo studies of the parasitological basis of chronic strongyloidiasis to show that barren females, via Douts of resumed fecundity with attendant autoinfection-supported population-turnover, maintain these persistent infections; (2) In vivo studies to test a simplified hypothesis that autoinfective larvae are larvae programmed to follow the homogonic developmental route, in contrast to the heterogonic route, but develop to infectivity precociously while still in the host. (3) Because the control of some alternative developmental pathways cannot be readily studied in in vivo nodels, we will employ in vitro alternatives. We will use a host-mimicking system to screen infective larvae with laser-ablated chemosensory neurons for the ability to react to host-like signals by resuming development We will ise larvae from the heterogonic pathway to identify chemo-, thermo- and mechanosensory neurons, used in host-finding, invasion, and migration, by laser microbeam ablation. (4) Studies to verify the identity of amphidial neurons in S. stercoralis, now based on structural and functional homology with Caenorhabditis elegans, with reverse genetics.